Atrial Fibrillation
Conditions
Brief summary
The purposes of this study are: 1. To evaluate the long-term safety of dabigatran etexilate 2. To assess the effect of a knowledge translation intervention on patient outcomes
Interventions
dabigatran high dose twice daily
dabigatran low dose twice daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participation in RE-LY, requires long term anticoagulation, provides written informed consent
Exclusion criteria
Permanent discontinuation of dabigatran during RE-LY
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Bleeding, Annualized Rate of Subjects With Major Bleeds | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Major bleeding must have satisfied one or more of the following criteria: * Bleeding associated with a reduction in hemoglobin of at least 20 g/L * Required transfusion of at least 2 units of blood or packed cells * Symptomatic bleeding in a critical area or organ: intraocular, intraspinal, intramuscular with compartment syndrome, retroperitoneal, intra-articular, pericardial, gastrointestinal Major bleed were classified as life-threatening if they met one or more of the following criteria: * Reduction in hemoglobin of at least 50 g/L * Transfusion of at least 4 units of blood or packed cells * Symptomatic intracranial bleeding, either subdural or intracerebral * Associated with hypotension requiring use of intravenous inotropic agents * Required surgical intervention to stop bleeding * Resulted in death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non CNS Systemic Embolism (SEE), Annualized Rate of Subjects With Non-CNS SEE | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Systemic embolism was an acute vascular occlusion of the extremities or any organ (kidneys, mesenteric arteries, spleen, retina or grafts), and was to be documented by angiography, surgery, scintigraphy, or autopsy. |
| Pulmonary Embolism (PE), Annualized Rate of Subjects With PE | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Pulmonary Embolism was generally documented by one of the following: 1. an intraluminal filling defect in segmental or more proximal branches on spiral CT scan 2. an intraluminal filling defect or an extension of an existing defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram 3. a perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS) 4. inconclusive spiral CT, pulmonary angiography or lung scintigraphy with demonstration of DVT in the lower extremities by compression ultrasound or venography. |
| Acute Myocardial Infarction (MI), Annualized Rate of Subjects With MI | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. a. In subjects not undergoing PCI or CABG a subject should have fulfilled at least 2 of the following: i. Typical prolonged severe chest pain or related symptoms or signs suggestive of MI. ii. Elevation of troponin or CK-MB to more than upper level of normal (ULN) or, if CK-MB was elevated at baseline, re-elevation to more than 50% increase above the previous level. iii. Development of significant Q-waves in at least 2 adjacent ECG leads. b. After percutaneous coronary intervention (within 24h). c. After coronary artery bypass grafting (within 72h). d. Silent myocardial infarction. e. Myocardial infarction could also have been demonstrated at autopsy. |
| Deep Vein Thrombosis, Annualized Rate of Subjects With DVT | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Deep Vein Thrombosis (DVT) was generally documented by one of the following: 1. abnormal compression ultrasound (CUS), 2. an intraluminal filling defect on venography. |
| Death, Annualized Rate of Subject Death | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Deaths were classified as being vascular (sudden/arrhythmic, pump failure death, or other vascular, including bleeding) or non-vascular, due to other specified causes (e.g., malignancy), or of unknown etiology. |
| Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE) | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. |
| Stroke, Annualized Rate of Subjects With Stroke | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Stroke was an acute onset of a focal neurological deficit of presumed vascular origin lasting for 24 hours or more or resulting in death. The stroke was categorized as ischemic or hemorrhagic or cause unknown based on computerized tomography (CT), magnetic resonance (MR) scanning or autopsy. Fatal stroke was defined as death from any cause within 30 days of stroke. Severity of stroke was assessed by modified Rankin score at discharge from hospital |
| Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE), Pulmonary Embolism (PE), Myocardial Infarction, Vascular Death | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. |
| Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE), Pulmonary Embolism (PE), Myocardial Infarction (MI), All Cause Death and Major Bleed | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. |
| Annualized Rate of Subjects With Minor Bleeds | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Minor bleeds were clinical bleeds that did not fulfill the criteria for major bleeds. Minor bleeds were classified as associated with study medication discontinuation (temporary or permanent) or not. |
| Annualized Rate of Subjects With Any Bleeds (Major Plus Minor) | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. |
| Annualized Rate of Subjects With Intra-Cranial Hemorrhage (ICH) | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. |
| Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE) and All Cause Death | up to 43 months | Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. |
Countries
Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Malaysia, Netherlands, Norway, Philippines, Poland, Portugal, Romania, Russia, Singapore, Slovakia, South Korea, Sweden, Switzerland, Taiwan, Thailand, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 5897 subjects were enrolled (rolled over from RE-LY trial), and 5891 were entered in this study. There were 8 subjects not treated; therefore 5883 subjects comprise the 'started' treatment group.
Participants by arm
| Arm | Count |
|---|---|
| Dabigatran 110 mg Dabigatran etexilate 110 mg twice daily | 2,914 |
| Dabigatran 150 mg Dabigatran etexilate 150 mg twice daily | 2,937 |
| Total | 5,851 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 111 | 121 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Elevated LFT results | 7 | 3 |
| Overall Study | Excluded from analysis | 13 | 19 |
| Overall Study | Hospitalization due to surgery | 37 | 40 |
| Overall Study | Hospitalization (not including surgery) | 18 | 17 |
| Overall Study | Major/minor bleed | 30 | 44 |
| Overall Study | Missing | 1 | 0 |
| Overall Study | Other reason not defined above | 5 | 5 |
| Overall Study | Outcome event - other | 33 | 25 |
| Overall Study | Patient elected | 7 | 9 |
| Overall Study | Patient refused to take study medication | 65 | 76 |
| Overall Study | Physician Decision | 47 | 38 |
| Overall Study | Procedure | 6 | 7 |
| Overall Study | Protocol Violation | 3 | 11 |
| Overall Study | Reduced creatinine clearance | 53 | 55 |
| Overall Study | Site closed | 4 | 3 |
| Overall Study | Site closed for cause | 19 | 19 |
| Overall Study | Withdrawal by Subject | 21 | 25 |
Baseline characteristics
| Characteristic | Dabigatran 110 mg | Dabigatran 150 mg | Total |
|---|---|---|---|
| Age, Continuous | 73.1 years STANDARD_DEVIATION 8.4 | 73.1 years STANDARD_DEVIATION 8.4 | 73.1 years STANDARD_DEVIATION 8.4 |
| Sex: Female, Male Female | 1000 Participants | 1026 Participants | 2026 Participants |
| Sex: Female, Male Male | 1914 Participants | 1911 Participants | 3825 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 1,028 / 2,914 | 1,106 / 2,937 |
Outcome results
Primary
Major Bleeding, Annualized Rate of Subjects With Major Bleeds
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Major bleeding must have satisfied one or more of the following criteria: * Bleeding associated with a reduction in hemoglobin of at least 20 g/L * Required transfusion of at least 2 units of blood or packed cells * Symptomatic bleeding in a critical area or organ: intraocular, intraspinal, intramuscular with compartment syndrome, retroperitoneal, intra-articular, pericardial, gastrointestinal Major bleed were classified as life-threatening if they met one or more of the following criteria: * Reduction in hemoglobin of at least 50 g/L * Transfusion of at least 4 units of blood or packed cells * Symptomatic intracranial bleeding, either subdural or intracerebral * Associated with hypotension requiring use of intravenous inotropic agents * Required surgical intervention to stop bleeding * Resulted in death
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Major Bleeding, Annualized Rate of Subjects With Major Bleeds | 2.79 percentage of subject-years |
| Dabigatran 150 mg | Major Bleeding, Annualized Rate of Subjects With Major Bleeds | 3.59 percentage of subject-years |
p-value: 0.005595% CI: [0.64, 0.93]Regression, Cox
Secondary
Acute Myocardial Infarction (MI), Annualized Rate of Subjects With MI
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. a. In subjects not undergoing PCI or CABG a subject should have fulfilled at least 2 of the following: i. Typical prolonged severe chest pain or related symptoms or signs suggestive of MI. ii. Elevation of troponin or CK-MB to more than upper level of normal (ULN) or, if CK-MB was elevated at baseline, re-elevation to more than 50% increase above the previous level. iii. Development of significant Q-waves in at least 2 adjacent ECG leads. b. After percutaneous coronary intervention (within 24h). c. After coronary artery bypass grafting (within 72h). d. Silent myocardial infarction. e. Myocardial infarction could also have been demonstrated at autopsy.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Acute Myocardial Infarction (MI), Annualized Rate of Subjects With MI | 0.72 percentage of subject-years |
| Dabigatran 150 mg | Acute Myocardial Infarction (MI), Annualized Rate of Subjects With MI | 0.66 percentage of subject-years |
Secondary
Annualized Rate of Subjects With Any Bleeds (Major Plus Minor)
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Annualized Rate of Subjects With Any Bleeds (Major Plus Minor) | 9.44 percentage of subject-years |
| Dabigatran 150 mg | Annualized Rate of Subjects With Any Bleeds (Major Plus Minor) | 11.20 percentage of subject-years |
Secondary
Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE)
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE) | 1.60 percentage of subject-years |
| Dabigatran 150 mg | Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE) | 1.47 percentage of subject-years |
p-value: 0.511995% CI: [0.84, 1.42]Regression, Cox
Secondary
Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE) and All Cause Death
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE) and All Cause Death | 4.40 percentage of subject-years |
| Dabigatran 150 mg | Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE) and All Cause Death | 4.02 percentage of subject-years |
p-value: 0.237195% CI: [0.94, 1.29]Regression, Cox
Secondary
Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE), Pulmonary Embolism (PE), Myocardial Infarction (MI), All Cause Death and Major Bleed
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE), Pulmonary Embolism (PE), Myocardial Infarction (MI), All Cause Death and Major Bleed | 6.65 percentage of subject-years |
| Dabigatran 150 mg | Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE), Pulmonary Embolism (PE), Myocardial Infarction (MI), All Cause Death and Major Bleed | 7.14 percentage of subject-years |
p-value: 0.224195% CI: [0.82, 1.05]Regression, Cox
Secondary
Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE), Pulmonary Embolism (PE), Myocardial Infarction, Vascular Death
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE), Pulmonary Embolism (PE), Myocardial Infarction, Vascular Death | 3.51 percentage of subject-years |
| Dabigatran 150 mg | Annualized Rate of Subjects With Composite Incidence of Stroke, Non CNS Systemic Embolism (SEE), Pulmonary Embolism (PE), Myocardial Infarction, Vascular Death | 3.32 percentage of subject-years |
p-value: 0.505295% CI: [0.89, 1.27]Regression, Cox
Secondary
Annualized Rate of Subjects With Intra-Cranial Hemorrhage (ICH)
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Annualized Rate of Subjects With Intra-Cranial Hemorrhage (ICH) | 0.28 percentage of subject-years |
| Dabigatran 150 mg | Annualized Rate of Subjects With Intra-Cranial Hemorrhage (ICH) | 0.33 percentage of subject-years |
Secondary
Annualized Rate of Subjects With Minor Bleeds
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Minor bleeds were clinical bleeds that did not fulfill the criteria for major bleeds. Minor bleeds were classified as associated with study medication discontinuation (temporary or permanent) or not.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Annualized Rate of Subjects With Minor Bleeds | 7.49 percentage of subject-years |
| Dabigatran 150 mg | Annualized Rate of Subjects With Minor Bleeds | 8.98 percentage of subject-years |
Secondary
Death, Annualized Rate of Subject Death
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Deaths were classified as being vascular (sudden/arrhythmic, pump failure death, or other vascular, including bleeding) or non-vascular, due to other specified causes (e.g., malignancy), or of unknown etiology.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Death, Annualized Rate of Subject Death | 3.18 percentage of subject-years |
| Dabigatran 150 mg | Death, Annualized Rate of Subject Death | 2.99 percentage of subject-years |
Secondary
Deep Vein Thrombosis, Annualized Rate of Subjects With DVT
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Deep Vein Thrombosis (DVT) was generally documented by one of the following: 1. abnormal compression ultrasound (CUS), 2. an intraluminal filling defect on venography.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Deep Vein Thrombosis, Annualized Rate of Subjects With DVT | 0.06 percentage of subject-years |
| Dabigatran 150 mg | Deep Vein Thrombosis, Annualized Rate of Subjects With DVT | 0.11 percentage of subject-years |
Secondary
Non CNS Systemic Embolism (SEE), Annualized Rate of Subjects With Non-CNS SEE
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Systemic embolism was an acute vascular occlusion of the extremities or any organ (kidneys, mesenteric arteries, spleen, retina or grafts), and was to be documented by angiography, surgery, scintigraphy, or autopsy.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Non CNS Systemic Embolism (SEE), Annualized Rate of Subjects With Non-CNS SEE | 0.25 percentage of subject-years |
| Dabigatran 150 mg | Non CNS Systemic Embolism (SEE), Annualized Rate of Subjects With Non-CNS SEE | 0.23 percentage of subject-years |
Secondary
Pulmonary Embolism (PE), Annualized Rate of Subjects With PE
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Pulmonary Embolism was generally documented by one of the following: 1. an intraluminal filling defect in segmental or more proximal branches on spiral CT scan 2. an intraluminal filling defect or an extension of an existing defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram 3. a perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS) 4. inconclusive spiral CT, pulmonary angiography or lung scintigraphy with demonstration of DVT in the lower extremities by compression ultrasound or venography.
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Pulmonary Embolism (PE), Annualized Rate of Subjects With PE | 0.10 percentage of subject-years |
| Dabigatran 150 mg | Pulmonary Embolism (PE), Annualized Rate of Subjects With PE | 0.12 percentage of subject-years |
Secondary
Stroke, Annualized Rate of Subjects With Stroke
Annualized event rate (%) = 100 \* No. subjects with event / subject-years. Subject-years = Sum (date of last visit - date of first dose + 1) of all subjects / 365.25. Stroke was an acute onset of a focal neurological deficit of presumed vascular origin lasting for 24 hours or more or resulting in death. The stroke was categorized as ischemic or hemorrhagic or cause unknown based on computerized tomography (CT), magnetic resonance (MR) scanning or autopsy. Fatal stroke was defined as death from any cause within 30 days of stroke. Severity of stroke was assessed by modified Rankin score at discharge from hospital
Time frame: up to 43 months
Population: SAF-FAS interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran 110 mg | Stroke, Annualized Rate of Subjects With Stroke | 1.39 percentage of subject-years |
| Dabigatran 150 mg | Stroke, Annualized Rate of Subjects With Stroke | 1.26 percentage of subject-years |